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Control of intervertebral disc degeneration via matrix-mediated delivery of platelet-derived growth factors

通过基质介导的血小板衍生生长因子的传递来控制椎间盘退变

基本信息

批准号：
10377961
负责人：
HICHAM M DRISSI
金额：
$ 42.39万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10377961
关键词：
Aftercare Apoptosis Apoptotic Autophagocytosis Autopsy Back Pain Becaplermin Biocompatible Materials Biological Assay Biological Response Modifier Therapy Biomechanics Blood Platelets Cells Chondrocytes Clinical Collagen Complementary DNA Cytokeratin Data Data Analyses Databases Disease Dose Drug Delivery Systems Economic Burden Encapsulated Engineering Exposure to FGF2 gene GAG Gene Gene Expression Generations Genes Genetic Transcription Goals Growth Factor Height Histologic Histology Homeostasis Human Hydrogels Image In Vitro Injectable Insulin-Like Growth Factor I Intervertebral disc structure Lasers Light Link Literature Low Back Pain LoxP-flanked allele Magnetic Resonance Imaging Measures Mediating Messenger RNA Microscopy Modality Modeling Molecular Mus Neck Pain Operative Surgical Procedures Orthopedics Oryctolagus cuniculus Outcome Outcome Measure Pathway Analysis Plasma Platelet-Derived Growth Factor Platelet-Derived Growth Factor alpha Receptor Platelet-Derived Growth Factor beta Receptor Pre-Clinical Model Prevalence Process Production Public Health Publishing Puncture procedure RUNX1 gene Reporting Role Seminal Serum Signal Transduction Signaling Molecule Societies Starvation Sulfate Symptoms Tail Testing Therapeutic Therapeutic Effect Tissues Transforming Growth Factor beta Transgenic Organisms Treatment Efficacy Validation Work base cell growth defined contribution density disability gain of function global health human disease improved in vivo inhibitor intervertebral disk degeneration knock-down laser capture microdissection mechanical properties monolayer mouse model new therapeutic target novel nucleus pulposus overexpression platelet-derived growth factor AB platelet-derived growth factor BB pre-clinical research preclinical study promoter response second harmonic senescence single-cell RNA sequencing small hairpin RNA societal costs transcription factor transcriptomics

项目摘要

Summary There is no successful biologic treatment for intervertebral disc degeneration (IDD). The goal of this proposal is to utilize a hydrogel-based engineering approach to deliver PDGF to intervertebral disc (IVD) tissue and establish PDGF as a potent inhibitor of IDD. We also aim to define the mechanisms underlying its effects on normal and diseased nucleus pulposus (NP) and annulus fibrosus (AF) cells using human IVDs as well as preclinical models of IDD. The scientific premise for the proposed work is a rigorous body of published evidence demonstrating that PDGF- BB, as well as PDGF-AB can stimulate disc cell growth and/or inhibit their programmed cell death in vitro. Our compelling preliminary data in vivo point to an anti-apoptotic effect of PDGF-BB in a rabbit puncture model, which led to restored disc height and enhanced mechanical properties of the treated discs compared to untreated controls. It is based on these encouraging data and other molecular preliminary data demonstrating that these anti-apoptotic effects may be mediated through the transcription factor Runx1, that we postulate the novel hypothesis that sustained exposure of the NP and AF to PDGF will repress IDD progression through controlling Runx1 activity. To test this hypothesis, we will first compare the effects of PDGF-BB and PDGF-AB on normal versus diseased human AF and NP cells cultured in high density. We will then determine the molecular mechanisms underlying the anti-degenerative effects of PDGF on disc cells through transcriptomic and functional analyses involving RUNX1 and other signaling molecules (Aim 1A). The validation of Runx1 function in PDGF-mediated effects will also be examined in vivo using a new gain of function mouse model (Aim 1B). In the second Aim, we will fabricate and validate the functionality of an injectable biomaterial capable of sustaining the exposure of disc cells to PDGF-BB (Aim 2A). We will then establish therapeutic modalities for long-term inhibition of IDD in vivo by PDGF-BB using a rabbit disc puncture model (Aim 2B). Our proposed work will provide seminal information about the mechanisms underlying PDGF’s effects on the IVD and the role of Runx1 in IDD. The mechanistic data will help identify new therapeutic targets to treat IDD.

总结目前还没有成功的生物治疗椎间盘退变（IDD）。这项提案的目的是是利用基于水凝胶的工程方法将PDGF递送至椎间盘（IVD）组织，建立PDGF作为IDD有效抑制剂。我们还旨在确定其影响的机制，正常和患病的髓核（NP）和纤维环（AF）细胞， IDD的临床前模型。这项工作的科学前提是一系列严格的已发表证据，证明PDGF- BB以及PDGF-AB可以刺激椎间盘细胞生长和/或抑制其体外程序性细胞死亡。我们令人信服的体内初步数据表明PDGF-BB在兔穿刺模型中具有抗凋亡作用，与未处理的相比，对照基于这些令人鼓舞的数据和其他分子初步数据，这些数据表明，抗凋亡作用可能是通过转录因子Runx 1介导的，我们假设新的假设持续暴露于PDGF的NP和AF将通过控制IDD进展来抑制IDD进展， Runx 1活动。为了验证这一假设，我们将首先比较PDGF-BB和PDGF-AB对正常人与病变人的作用。高密度培养的人AF和NP细胞。然后我们将确定潜在的分子机制通过转录组学和功能分析PDGF对椎间盘细胞的抗变性作用， RUNX 1和其他信号分子（Aim 1A）。Runx 1在PDGF介导效应中的功能验证将还使用新的功能获得小鼠模型（Aim 1B）在体内进行检查。在第二个目标中，我们将制造并验证能够维持椎间盘暴露的可注射生物材料的功能细胞转化为PDGF-BB（Aim 2A）。然后我们将建立长期抑制IDD的体内治疗模式使用兔椎间盘穿刺模型（Aim 2B）通过PDGF-BB。我们的计划工作将提供开创性的信息关于PDGF对IVD的作用机制以及Runx 1在IDD中的作用。机械论数据将有助于确定治疗IDD的新治疗靶点。